This project seeks to clarify the exact location and mechanism of synaptic transmission in the central and peripheral nervous system. It is carried out by examining synapses with the electron microscope and by determining the influence of various functional states on their structure. In the last year we have examined discharge of synaptic vesicles by using the freeze-fracture technique. These studies have shown that synaptic vesicles can be discharged only at specific points on the synaptic membrane and that these points are determined by specific structures within the membrane. We have also been able to produce direct evidence that synaptic vesicles discharge their contents by fusing with the synaptic membrane, a process well known in other secretory cells as exocytosis. Also, particulate structures, thought to be receptor molecules within the postsynaptic membrane, appear to be different at each chemical type of synapse, although more types of synapse must be examined before this conclusion is certain. One class of synaptic connection in the central nervous system is lacking in one strain of mouse, even though both components for this synapse are present and able to make synapses with other types of neuronal processes. Thus, formation of this synaptic type may be under genetic control. Future work will concentrate on how the molecular structure of synaptic membranes is developed.